Treatment of COVID-19 olfactory dysfunction with olfactory training, palmitoylethanolamide with luteolin, or combined therapy: a blinded controlled multicenter randomized trial

Abstract

Purpose: Few evidence-based therapies are available for chronic olfactory dysfunction after COVID-19. This study investigated the relative efficacy of olfactory training alone, co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT, an anti-neuroinflammatory supplement) alone, or combined therapy for treating chronic olfactory dysfunction from COVID-19.

Methods: This double-blinded controlled, placebo-controlled multicenter randomized clinical trial was conducted in 202 patients with persistent COVID-19 olfactory dysfunction of > 6 month duration. After a screening nasal endoscopy, patients were randomized to: (1) olfactory training and placebo; (2) once daily um-PEA-LUT alone; (3) twice daily um-PEA-LUT alone; or (4) combination of once daily um-PEA-LUT with olfactory training. Olfactory testing (Sniffin' Sticks odor identification test) was performed at baseline and at 1, 2, and 3 months. The primary outcome was recovery of over three points on olfactory testing, with outcomes compared at T₀, T₁, T₂ and T₃ across groups. Statistical analyses included one-way ANOVA for numeric data and chi-square for nominal data.

Results: All patients completed the study, and there were no adverse events. At 90 days, odor identification scores improved by > 3 points in 89.2% of patients receiving combined therapy vs. 36.8% receiving olfactory training with placebo, 40% receiving twice daily um-PEA-LUT alone, and 41.6% receiving once daily um-PEA-LUT alone (p < 0.00001). Patients receiving treatment with um-PEA-LUT alone demonstrated subclinical improvement (< 3 point odor identification improvement) more often than patients receiving olfactory training with placebo (p < 0.0001.) CONCLUSIONS: Olfactory training plus once daily um-PEA-LUT resulted in greater olfactory recovery than either therapy alone in patients with long-term olfactory function due to COVID-19.

Trial registration: 20112020PGFN on clinicaltrials.gov.

Level of evidence: 1b (Individual Randomized Clinical Trial).

Keywords: Anosmia; COVID-19; Clinical trial; Coronavirus; Hyposmia; Luteolin; Neuroinflammation; Olfactory training; PEA; PEA–LUT; Palmitoylethanolamide; Post-acute sequelae of COVID-19; Randomized trial; SARS-CoV-2; Smell disorders.

Fig. 1

Experimental design and randomization scheme with allocation of the patients across the 4 different groups. Allocation reflects double weighting in randomization for the putative gold standard (olfactory training + um-PEA–LUT). um-PEA–LUT ultramicronized palmitoylethanolamide with luteolin

Fig. 2

Rings show differences recovery within the four groups. um-PEA–LUT + olfactory training and um-PEA–LUT 1 sachet daily allowed for some recovery of the olfactory functions in 100% patients. PEA–LUT ultramicronized palmitoylethanolamide with luteolin

Fig. 3

Olfactory scores across groups. Maximal olfactory recovery was observed after 3 months of therapy in the patients who combined um-PEA–LUT and olfactory training. PEA–LUT ultramicronized palmitoylethanolamide with luteolin, OT olfactory training; “*”p < 0.05; “**”p < 0.01